The objective of this program is to define the molecular mechanisms that regulate fate choice and subtype specification in the developing vertebrate central nervous system. Insights into the molecular mechanisms of fate choice will have practical overtones for therapy of neurodegenerative diseases, spinal cord injury, multiple sclerosis and primary cancers of the brain. Three hypothesis-driven projects focus on bHLH transcription factors that direct formation of the dorsal and the ventral neural tube. This cohesive central theme is attacked by a program faculty with expertise that ranges from computer science, through developmental neurobiology to pediatric neurology. The projects are interactive and exploit economies of scale generated by core facilities for expression vectors and bioinformatics. In Subproject 0001, Drs. Michael Greenberg and Qiufu Ma focus upon the dorsal neural tube where the Ngn subfamily of proneural bHLH transcription factors regulate multiple aspects of neural development, including the timing of cell cycle exit, cell migration, neuronal connectivity, suppression of the glial cell fate, and the specification of neuronal subtype identity. Greenberg and Ma will test the hypothesis that, within the ventricular zone, Ngns function as latent transcription factors, and perhaps as repressors of transcription, until they are transiently activated by Erk-mediated phosphorylation. In Subproject 0002, Drs. Charles Stiles and David Rowitch will focus upon ventral neural tube where the bHLH transcription factors Olig1 and Olig2 regulate the fate choice to form neurons or oligodendrocytes. Though structurally similar and coordinately expressed, the two Olig genes have non-overlapping biological functions. Stiles and Rowitch will test the hypothesis that the distinct biological functions of Olig1 and Olig2 reflect differential interactions with transcription co-activator proteins. In Subproject 0003, Drs. Ma and Rowitch will lead Greenberg, Stiles and others through a genome wide reverse genetic screen for downstream transcription factors that are regulated by Ngu and Olig genes to control later maturation of specialized neurons and glia. One byproduct of this screen will be a genome wide map of transcription factor expression in developing neural tube. This atlas will be made accessible to the broader scientific community via a searchable web-based interface.